We have a new scientific mystery and we’ll find out the implications this autumn.
The new version of SARS2 spreading around the globe is called EG.5.1. Normally, when a new version of this virus spreads, it does so because it changed its Spike protein sufficiently to make the antibodies useless (immune evasion).
But then came XBB. And as I mentioned before, what you see with XBB is that an infection doesn’t induce neutralizing antibodies against it, in mice who have already been infected by the original strain.
And now we have a new study from Japan that looks at this, confirming this strange problem:
As of July 2023, EG.5.1 (a.k.a. XBB.18.104.22.168.1), a XBB subvariant bearing the S:Q52H and S:F456L substitutions, alongside the S:F486P substitution (Figure S1A), has rapidly spread in some countries. On July 19, 2023, the WHO classified EG.5 as a variant under monitoring. First, we showed that EG.5.1 exhibits a higher effective reproduction number compared with XBB.1.5, XBB.1.16, and its parental lineage (XBB.1.9.2), suggesting that EG.5.1 will spread globally and outcompete these XBB subvariants in the near future. We then addressed whether EG.5.1 evades from the antiviral effect of the humoral immunity induced by breakthrough infection (BTI) of XBB subvariants and performed a neutralization assay using XBB BTI sera. However, the 50% neutralization titer (NT50) of XBB BTI sera against EG.5.1 was comparable to those against XBB.1.5/1.9.2 and XBB.1.16. Moreover, the sensitivity of EG.5.1 to convalescent sera of XBB.1- and XBB.1.5-infected hamsters was similar to those of XBB.1.5/1.9 and XBB.1.16. These results suggest that the increased Re of EG.5.1 is attributed to neither increased infectivity nor immune evasion from XBB BTI, and the emergence and spread of EG.5 is driven by the other pressures. We previously demonstrated that Omicron BTI cannot efficiently induce antiviral humoral immunity against the variant infected. In fact, the NT50s of the BTI sera of Omicron BA.1, BA.2, and BA.5 against the variant infected were 3.0-, 2.2-, and 3.4-fold lower than that against the ancestral B.1.1 variant, respectively. However, strikingly, we found that the NT50 of the BTI sera of XBB1.5/1.9 and XBB.1.16 against the variant infected were 8.7- and 8.3-fold lower than that against the B.1.1 variant. These results suggest that XBB BTI cannot efficiently induce antiviral humoral immunity against XBB subvariants.
In other words, you see that the antibodies from the XBB variants are as good at stopping those variants, as they are at stopping EG.5.1. That’s not what normally happens. A new variant normally emerges because it changed its Spike protein enough to make the most potent antibodies most people deploy useless.
But now we’ve run into a situation where this apparently isn’t necessary anymore. Which raises the big question:
So, if this version isn’t better at dodging the antibodies, what is it better at that apparently allows it to rapidly replace its XBB ancestors?
Well, it turns out this new variant looks an awful lot like the Delta variant:
The reason Delta ever took over had less to do with antibody evasion and more to do with the fact that it rapidly produced a lot of copies of itself. This meant that if people’s antibody concentrations were low enough (ie many elderly a few months after vaccination), the virus would spread through their body before concentrations could rise enough to suppress the viral load. It’s only with Omicron, when the Spike in the vaccines became truly mismatched.
But I think there’s another issue we’re dealing with, which would also explain why the virus suddenly seemed to fade away months ago across the world and is now rapidly returning, without having substantially changed its Spike protein: Improved interferon suppression.
If antibodies are high, the virus can’t infect a person. And because people now have antibodies against just about every viral protein and a wide variety of variants, it’s not easy to mutate around that.
And so rather than mutating to avoid antibodies, another strategy for survival would be to wait until the antibodies fade and then to infect people in a manner that prevents the infected cells from sending a warning signal that they have been infected. That’s the route that EG.5.1* seems to represent.
And yet, the other route can not be ruled out. It’s also perfectly possible for a new version of SARS2 to emerge that is once again so different from the recently circulating varieties that the antibody response proves to be useless again. That would be an Omicron-like event. It seems that yesterday, such a discovery may have been made.
In a context where everyone has antibodies against this virus and we constantly try to raise antibodies, any such saltation that emerges, like this saltation discovered yesterday with at least 30 amino acid mutations in Spike, will have a huge selective advantage, regardless of its own intrinsic transmissibility.
And the worst case scenario you may be faced with as a result, is a Dengue-like serotypes scenario. I did not invent this myself, it was warned about here, as well as by a number of other articles.
What happens in a serotypes scenario, is that you end up with multiple very distinct looking SARS2 viruses circulating simultaneously. But importantly, antibodies against Serotype 1 induced by an infection, would cause antibody dependent enhancement for Serotype 2 and vice versa. And because these Serotypes depend on each other, they would continue to circulate simultaneously.
Such serotypes could emerge pretty much instantaneously, from persistent infections, or spillovers from animal populations. If the new variant discovered yesterday proves fit enough to spread through the population (still uncertain), it may reveal itself to be such a serotype strain: One that does not replace the XBB family but co-exists besides it, both feeding off each other.
The reality is that antibodies against Spike, are just not a sustainable way for our immune systems to deal with the circulation of the virus. Only about 10% of the population is infected by influenza in a typical year, so you don’t have to worry too much about antibody mismatches.
But with SARS-COV-2, we see that the average person is infected at least twice a year, by rapidly evolving variants. In such a scenario, antibodies against the Spike protein are not going to solve the problem for us. By training people’s immune systems to induce a strong IgG antibody response against the Spike protein, we merely made the pandemic worse: We taught the immune system to bring the wrong weapon to the battle.
For viruses like this, the innate immune system has to do the job.